A decline in core cognitive functions of attention, memory, and learning ability is commonly observed in neurodegenerative conditions such as Alzheimer's disease. These deficits can be partially reversed by cholinergic agents, for example acetylcholine agonists or acetylcholinesterase inhibitors. Cholinergic agents have also shown promise in enhancing recovery of cognitive functions after brain insult or disease, as in the case of Traumatic Brain Injury. Despite the known effectiveness of cholinergic agents, the neuronal mechanisms mediating cognitive performance that are targeted by ACh are poorly understood. The prefrontal cortex is known to be essential for higher cognitive functions, yet it is unknown how prefrontal neuronal activity mediating cognitive performance is affected by ACh levels. Taking advantage of recent technical innovations and experimental findings, we propose to use a non-human primate model to perform neurophysiological recordings from a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents. The project relies on monitoring neuronal discharges from multiple cortical sites each day, in the same animals, before and after pharmacological intervention. This research will identify the aspects of neuronal activity that co-vary with behavioral performance during execution of cognitive tasks and will determine which of these are degraded by ACh antagonists and improved by ACh enhancers. Successful completion of the project will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation after neurodegenerative conditions and brain trauma. PUBLIC HEALTH RELEVANCE: Regulation of acetylcholine levels in the brain has been linked to the cognitive impairments associated with ageing, dementia, and schizophrenia. The proposed research will rely on a primate model to determine the effects of acetylcholine levels in a brain area critical for higher cognitive functions, the lateral prefrontal cortex. Successful completion of the project will provide a novel, primate model for the evaluation of different types of drugs as they relate to cognitive performance and rehabilitation.